In vivo‐ and in silico‐driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors
| Autor: | Hamada S. Abulkhair, Hany E.A. Ahmed, Adel Ghiaty, Memy H. Hassan, Ashraf H. Bayoumi, Mohamed F. Zayed, Mona S. El-Zoghbi, Salwa Elmeligie, Eman N. Akl, Ahmed El-Morsy, Khaled El-Adl |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_treatment In silico Pharmaceutical Science Pharmacology 01 natural sciences Mice Structure-Activity Relationship Perampanel chemistry.chemical_compound Seizures In vivo Quinoxalines Drug Discovery medicine Animals alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Druglikeness 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Anticonvulsant Agent Anticonvulsant chemistry Docking (molecular) Pentylenetetrazole Anticonvulsants Pharmacophore Injections Intraperitoneal |
| Zdroj: | Archiv der Pharmazie. 354:2000449 |
| ISSN: | 1521-4184 0365-6233 |
| DOI: | 10.1002/ardp.202000449 |
| Popis: | The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles. |
| Databáze: | OpenAIRE |
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